Effect of serotonin transporter genotype on carbon dioxide-induced fear-related behavior in mice

Nicole K. Leibold*, Daniel L. A. van den Hove, Magdalena T. Weidner, Gordon F. Buchanan, Harry W. M. Steinbusch, Klaus-Peter Lesch, Koen R. J. Schruers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review



Inhaling 35% carbon dioxide induces an emotional and symptomatic state in humans closely resembling naturally occurring panic attacks, the core symptom of panic disorder. Previous research has suggested a role of the serotonin system in the individual sensitivity to carbon dioxide. In line with this, we previously showed that a variant in the SLC6A4 gene, encoding the serotonin transporter, moderates the fear response to carbon dioxide in humans. To study the etiological basis of carbon dioxide-reactivity and panic attacks in more detail, we recently established a translational mouse model.


The purpose of this study was to investigate whether decreased expression of the serotonin transporter affects the sensitivity to carbon dioxide.


Based on our previous work, wildtype and serotonin transporter deficient (+/-, -/-) mice were monitored while being exposed to carbon dioxide-enriched air. In wildtype and serotonin transporter +/- mice, also cardio-respiration was assessed.


For most behavioral measures under air exposure, wildtype and serotonin transporter +/- mice did not differ, while serotonin transporter -/- mice showed more fear-related behavior. Carbon dioxide exposure evoked a marked increase in fear-related behaviors, independent of genotype, with the exception of time serotonin transporter -/- mice spent in the center zone of the modified open field test and freezing in the two-chamber test. On the physiological level, when inhaling carbon dioxide, the respiratory system was strongly activated and heart rate decreased independent of genotype.


Carbon dioxide is a robust fear-inducing stimulus. It evokes inhibitory behavioral responses such as decreased exploration and is associated with a clear respiratory profile independent of serotonin transporter genotype.

Original languageEnglish
Pages (from-to)1408-1417
Number of pages10
JournalJournal of Psychopharmacology
Issue number12
Publication statusPublished - Dec 2020


  • Panic attacks
  • panic disorder
  • serotonin transporter
  • carbon dioxide

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